The most common inherited disorder causing blindness in man is retinitis pigmentosa, a family of diseases in which photoreceptor cells of the retina degenerate slowly and progressively over a period of years, and pigmented cells move into the degenerating retina. Similar inherited diseases are found in several laboratory animals. The major long-term objective of our research program is to elucidate the cellular mechanisms that lead to photoreceptor cell death in hereditary retinal degenerations. Understanding these mechanisms should ultimately lead to therapies to retard or even prevent the loss of these cells. We propose to study the effects of 5 mutations that cause 6 different forms of inherited retinal degeneration. Thee animal models ar the RCS rat and the following mutant mice: retinal degeneration, nervous, Purkinje cell degeneration and retinal degeneration slow (both homozygous and heterozygous forms).
OUr specific aims are generally to define the phenotypic characteristics (i.e., cytopathologic features and sequence of changes that occurs in each of the mutants. To accomplish this we will use method s of quantitative light and electron microscopy, histochemistry and immunocytochemistry, as well as the application of these methods to the retinas of experimental chimeras. Analysis of he interphotoreceptor matrix will be a major focus of many of the studies. Mechanisms controlling normal turnover of the interphotoreceptor matrix will be addressed as well. The experimental chimeras will be used further to determine if some genetic defects can be ameliorated or reversed. In addition, the interphotoreceptor matrix will be examined in postmortem donor eyes of patients with different forms of retinitis pigmentosa. Lastly, a murine model will be sought for experimental studies on Usher's Syndrome, the major cause of combined deafness and blindness in the United States.
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